Treatment

General

Treatment depends on the type and extent of amyloidosis and the associated organ damage.

“Precursor-product” concept as a treatment principle

The “precursor product” concept is central to the treatment. The idea here is that further growth of amyloid deposits will come to a halt when there is no longer any supply of precursor proteins.

Thus, AA-type treatment aims to minimize the levels of the inflammatory protein Serum Amyloid A (SAA) by maximal treatment of the underlying inflammatory process.

In the AL type, treatment aims to destroy the clonal plasma cells responsible for the production of the free light chains that deposit in the form of amyloid.

ATTR amyloidosis is treated with medications that stabilize the protein transthyretin or reduce its production in the liver, so that it can deposit less as amyloid. A recent development is medicines that work according to the “gene-silencing” technique, patisiran and inotersen. Since January 1, 2019, the drug patisiran, which works on this principle, has been available in the Netherlands for patients with hereditary ATTR amyloidosis and stage I or II polyneuropathy. A registration procedure for the drug inotersen is currently underway in the Netherlands.

Organ supportive therapy

In addition to the treatment that focuses on the underlying process, it is of course also necessary to provide supportive treatment for the organ dysfunction caused by the deposition of the amyloid. This can vary a lot, such as treatment of right ventricular decompensation, but also treatment of nephrotic syndrome with salt restriction, careful use of diuretics and possible ACE inhibitors or NSAIDs. In orthostatic hypotension, erythropoietin can sometimes be useful in addition to fludrocortisone. Caution is advised with agents such as amitriptyline for neuropathic pain because of the potential adverse effects on rhythm and tension. Good nutrition (often in consultation with a dietitian) is necessary for impaired absorption and other gastrointestinal problems (including intestinal pseudo-obstruction).

Treatment options

AA amyloidosis

The treatment of AA amyloidosis is aimed at reducing the level of the inflammatory protein Serum amyloid A (SAA) to low as possible by maximal treatment of the underlying inflammatory process.

This can be done, for example, by the effective surgical or antibiotic treatment of an infection source, by chemotherapy in Hodgkin’s disease, and effective suppression of inflammation (and thus SAA levels in the blood) in autoimmune and auto-inflammatory diseases such as rheumatoid arthritis and Crohn’s disease or familial Mediterranean fever. The arrival of medicines known as biologicals, which very specifically inhibit inflammatory processes, has meant that AA amyloidosis is much less common in the Netherlands.

AL amyloidosis

In the AL type, treatment aims to destroy the clonal plasma cells responsible for the production of the free light chain that deposits in the form of amyloid. The plasma cells are destroyed by chemotherapy, if possible followed by a transplant of the patient’s own stem cells. You can find more information about the treatment of AL amyloidosis on the website of our hematology department.

Wild-type ATTR-amyloidosis (ATTRwt)

Due to aging processes, the protein transthyretin can become unstable, fold incorrectly and then form amyloid. This type of amyloidosis can be treated with medications that stabilize the protein transthyretin, making it less likely to form amyloid. These drugs, diflunisal and tafamidis, cannot cure the disease but do inhibit disease progression. Recent studies have shown that the survival of patients treated with tafamidis was better than that of patients treated with a placebo (a pill without active ingredients). The condition and quality of life deteriorated less rapidly in patients treated with tafamidis. Tafamidis was especially effective in people who still had relatively few heart failure complaints (NYHA I-II). Based on these data, it is unlikely that end-stage heart failure (NYHA IV) patients will have any survival benefit from tafamidis treatment. A registration procedure for tafamidis for people with wild-type ATTR amyloidosis is currently underway in the Netherlands. Treatment with tafamidis is available in a study setting.

Hereditary ATTR amyloidosis (ATTRv)

In hereditary ATTR amyloidosis, a mutation (error) in the gene for transthyretin causes this protein to be unstable, fold incorrectly and to form amyloid. In case of hereditary ATTR amyloidosis, disease progression can be inhibited with drugs that stabilize transthyretin. Tafamidis is registered in the Netherlands for people with stage I polyneuropathy due to hereditary ATTR amyloidosis.
Transthyretin is, among other things, produced in the liver cells. What the protein should look like is recorded in the TTR gene. For the production of transthyretin, the TTR gene is read in the cell nucleus and converted into messenger RNA (mRNA). This mRNA is used to tell the ribosome which amino acids the protein transthyretin must consist of.

In people with hereditary ATTR amyloidosis, there is a mutation in the gene for transthyretin that produces abnormal mRNA and ultimately abnormal transthyretin.

The results of research into drugs that work according to the principle of gene silencing have recently been published. These drugs, patisiran and inotersen, enter the bloodstream after administration and are absorbed into the liver cells. In the liver cells, these drugs destroy the mRNA for transthyretin. In this way, selectively, the production of transthyretin is drastically reduced, reducing the amount of transthyretin entering the bloodstream and thus less transthyretin that can misfold and deposit as amyloid.

Research has shown that these drugs stop the progression of polyneuropathy in many cases and also have a beneficial effect on the amyloid in the walls of the heart. Whether these drugs also have an effect on the development of amyloid in the eye or in the brain is not yet known.

Since January 1, 2019, the drug patisiran has been registered in the Netherlands for patients with stage I and II polyneuropathy. The drug should in principle be administered through the bloodstream every three weeks for life.

At the end of 2019, a study was started at the Center of Expertise into the effectiveness and safety of a drug that also works according to the principle of “gene silencing”, but which only needs to be administered subcutaneously once every three months.

Local amyloidosis

In the local forms of amyloidosis, surgery or radiotherapy are the only options for influencing the process and, if possible, stopping it. The chances are that the amyloid will return after surgery. It is often necessary to repeat the surgical removal of the amyloid one or more times before the process appears to cease. In very rare cases, the local deposition of amyloid is part of a systemic amyloidosis (often the AL type) or related to a local monoclonal plasma cell proliferation. In these cases, treatment naturally focuses on the causal process.

Monitoring

After the diagnosis has been made, there will be regular checks during the follow-up, known as the monitoring. These controls are important for several reasons, namely:

1. To detect (in carriers of a mutation) the disease in good time and then to be able to make adjustments in the treatment/strategy.
2. To detect disease progression in good time and to make adjustments in treatment/strategy.
3. To be able to determine the effect of the treatment instituted and, if necessary, to make adjustments to the treatment/strategy.
4. To be able to identify side effects of the treatment and, if necessary, to make adjustments to the treatment/strategy.
5. To be able to identify complaints or symptoms caused by the disease and to relieve/treat them as effectively as possible.
6. To inform patients about the latest developments in the field of (the treatment of) amyloidosis and possibilities to participate in research into new medicines.
7. To participate in scientific research into various aspects of amyloidosis in order to improve care for patients in the future.
8. The frequency of check-ups, the type of examination required and the medical specialists involved will depend on the type and extent of amyloidosis and associated organ damage. Checks take place at regular intervals in the Amyloidosis Expertise Center and, if necessary, interim checks can be carried out in another hospital closer to home (one of the affiliated treatment centers).

To clarify how routine monitoring works, below are some examples of the planning of monitoring for different types of amyloidosis. Our primary goal in each individual patient is understand both the severity and course of the disease and the long-term effect of treatment (also called personalized medicine). As a basis (A), a plan that can apply to all patients with that type of amyloid, supplemented with specific checks that apply to that patient, in particular, with their symptoms and organ involvement, with specific checks (B) appropriate for the stage of the disease and the effect of the treatment being initiated. Every year it is necessary to evaluate the state of affairs and, if necessary, the plan is adapted to the situation.

Example of an AA patient: a 50-year-old man with severe erosive rheumatoid arthritis for 20 years. The disease is characterized by renal dysfunction (clearance 50 ml/min) and strong proteinuria (8 grams/24h). Treatment with MTX, anti-TNF, salt restriction and ACE inhibition.
A. Every three months monitoring of blood pressure, oedema, weight, joint complaints and joint examination, blood count, CRP, SAA, AF, GGT, kidney function, albumin and proteinuria. Annual check of NT-proBNP, troponin T and TSH and, if necessary, X-rays of joints. Check-ups every two to five years with ECG, echocardiogram, fibroscan of the liver, SAP scan and fat biopsy.
B. Medication sufficiently effective? Possibly switch to tocilizumab? In due course is dialysis or kidney transplant needed? Infections with biologicals? Indications for artificial joints?

Example of an AL patient: a 60-year-old woman with AL-lambda amyloidosis characterized by hepato- and splenomegaly, liver function disorders (AF 600, GGT 900, total bilirubin 40, albumin 32 and coagulation disorders) with a VLK lambda of 130, kappa 12, IgG-lambda 3.2, Bence Jones proteinuria 60 mg/24h and 8% plasma cell dyscrasia in bone marrow, 70% of which are lambda-positive plasma cells. Started chemotherapy.
A. Every three months monitoring of blood count, VLK kappa and lambda, AF, GGT, total bilirubin, renal function, albumin, NT-proBNP, troponin T and urine albumin. Annual monitoring of TSH and M protein, 24 hour urine, ECG, echocardiogram, fibroscan of the liver, SAP scan and fat biopsy. Bone marrow check on indication.
B. Discuss during this treatment when the effect of the chemo can be expected, when it is necessary to switch to another treatment and whether, in addition, stem cell transplantation should be considered. Is the result satisfactory (complete response) or good enough (VGPR), only partial (PR), or is no response shown? How to proceed?

Example of an ATTR patient: a 40-year-old male with a Val30Met mutation, grade 1 polyneuropathy, slightly increased NT-proBNP, positive cardiac uptake on the bone scan and gastric emptying disorders. Started treatment with tafamidis.
A. Checking of complaints every six months, physical examination (weight, orthostasis, edema), blood count, CRP, TTR, NT-proBNP, troponin T, creatinine, urine for albumin. Annual check of the NIS, fat biopsy, possible bone scan, echocardiogram, MRI with T1 mapping, MIBG. Record CNS situation, including with a Pib scan and MRI.
B. Depending on any progression, if any, (nerves, heart, autonomic, eyes) consider switching to a higher dose (80 mg) of tafamidis or to a gene silencer such as patisiran.